Neuromedin U (NMU) was first isolated, as a peptide consisting of 25 amino acid residues or as a peptide consisting of 8 amino acid residues, from the pig small intestine using uterine smooth muscle contraction activity as an index. These peptides are named porcine NMU-25 or porcine NMU-8, based on the number of amino acid residues. Porcine NMU-8 is a cleavage product of porcine NMU-25 and consists of the C-terminal 8 residues of porcine NMU-25.
Similarly, NMU-25 is known in humans. The amino acid sequence of the C-terminal 8 residues of human NMU-25 is the same as that of the C-terminal 8 residues of porcine NMU-8.
Rat NMU consists of 23 amino acid residues, and is named NMU-23. The amino acid sequence of the C-terminal 8 residues of rat NMU-23 differs from that of the C-terminal 8 residues of porcine NMU-8 by one amino acid residue.
As a receptor for NMU, FM3, which is an orphan GPCR, was initially identified; subsequently, TGR1 was identified. Today, these receptors are called NMUR1 and NMUR2, respectively. FM3 is primarily distributed in the intestinal tract, whereas TGR1 is localized in the hypothalamus.
As a receptor for TGR1, a novel peptide has been isolated from rat brain. Since this peptide is localized in the suprachiasmatic nucleus within the hypothalamus, it was named neuromedin S (NMS), using the initial letter of the suprachiasmatic nucleus.
Human NMS consists of 33 amino acid residues, and the amino acid sequence of the C-terminal 8 amino acid residues are the same as the amino acid sequence of the C-terminal 8 residues of rat NMU-23.
NMUR1 and NMUR2 exhibit similar affinity to NMU, NMS, and NMU-8. It has been suggested that these receptors strongly recognize the amino acid sequence of the C-terminal 8 residues, the sequence of which is common to NMU and NMS.
An intracerebroventricular administration of rat NMU-23 in rats induces food intake suppression. A local injection of NMU to the paraventricular nucleus (PVN) or arcuate nucleus (ARC) has also been reported to induce an anorectic activity as in the case of its intracerebroventricular administration; therefore, the action sites of NMU are assumed to be PVN and ARC. Further, an intracerebroventricular administration of anti-NMU antibody has shown to increase food intake, suggesting that the central NMU produces physiological effects that suppress food intake. It has also been reported that NMU KO mice exhibited an obese phenotype, and that mice over-expressing NMU exhibited lower body weight and reduced food intake. This clarifies the physiological significance of endogenous NMU.
It has further been reported that an intracerebroventricular administration of NMU causes an elevation of body temperature, generation of heat, and elevation of oxygen consumption. These activities are assumed to be due to sympathetic activation of adipose tissue and muscle system.
It has also been reported that suppression of gastric acid secretion and suppression of gastric emptying are caused by an intracerebroventricular administration of NMU. These activities are assumed to be due to the central effects via CRH secretion. These activities result in reduced food intake.
It has not yet been examined in detail how a peripheral administration of NMU causes an action on the intestinal tract; however, considering that NMUR1 is expressed in the intestinal tract, it can be assumed that the peripheral administration of NMU causes a certain action on the intestinal tract. Based on this assumption, action on the stomach or intestinal tract caused by NMU peripheral administration was examined, and colon-specific prokinetic activity has been discovered.
Patent Literature (PTL) 1 and 2 disclose that an anorectic effect is achieved by peripheral administration of NMU.
The present inventors also discovered on their own accord that NMU-23 induces an anorectic activity via peripheral administration. In contrast, NMU-8 does not induce an anorectic activity via peripheral administration, although NMU-8 has a sufficiently strong agonist activity on the receptors, NMUR1 and NMUR2.
In order for a neuromedin U to be useful as an anorectic agent, it is very important that a neuromedin U induces a high anorectic activity even when administered in a usual manner, for example, peripherally.
As PEG derivatives, which are used for chemical modifications in the field of medicine, various compounds are known.